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Synthesis and antimalarial activity of pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives

a technology of pyrrolo[3,2-f]quinazoline and derivatives, which is applied in the field of new compounds, can solve the problems of low therapeutic index of compound 1 and severely limited its value as an antimalarial agent, and the situation of malaria control is rapidly worsening

Inactive Publication Date: 2006-05-04
UNITED STATES OF AMERICA THE AS REPRESENTED BY THE SEC OF THE ARMY
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Problems solved by technology

The situation of malaria control is rapidly worsening mainly due to non-availability of effective drugs and development of drug resistance to the existing first line drugs [4, 5].
Furthermore, the usefulness of many newer antimalarial drugs was impaired by their side effects.
The low therapeutic index of compound 1 has severely limited its value as an antimalarial agent.
In addition to high host toxicity, the lead compound 1 is sparingly soluble in common organic solvents and water, a highly undesirable physical property for large scale synthesis and purification.
The parent compound 1 is sparingly soluble in either water or common organic solvents, which is a challenging problem to overcome during its large scale preparation.

Method used

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  • Synthesis and antimalarial activity of pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives
  • Synthesis and antimalarial activity of pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives
  • Synthesis and antimalarial activity of pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives

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Embodiment Construction

[0012] In this invention, we have initially synthesized a series of alkylcarbamates of WR227825 (2a-m) as shown in Table 1. All of the carbamates prepared, except 2-chlorobenzylcarbamate 2m, showed low in vitro activities against D-6, RCS, W-2 and TM91C235 clones of Plasmodium falciparum (Table 3), yet retained high in vivo activities against P. berghei (Table 4-5) in mouse, suggesting that carbamates of WR227825 may act as prodrugs which generate parent compound 1 in vivo. However, the carbamates all showed much higher tolerance (less toxic) than the parent molecule in the mice tests. Further, we explored the potential of carboxamides as a way to improve the therapeutic index by synthesizing a series of alkylcarboxamides and succinimides of WR227825 (Table 2) (3a-g), with which the amino groups, essential for DHFR inhibition, were tied down with acyl functions. Contrary to the existing knowledge of structure activity relation of antifolates which the free amino groups are essential...

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Abstract

The invention relates to derivatives of pyrroloquinazolinediamine, more specifically derivatives of 7-(substituted)-7H-pyrrolo[3,2-F] quinazoline-1,3-diamines that are non-toxic and are also effective in the treatment of malaria, including P. falciparum and P. vivax strains. The derivatives are certain carbamate derivatives, succinimide derivatives, alkylcarboxamides derivatives and acetamide derivative, phthalimides, alkylamines and all other amide and imide derivatives and their 1-hydroxy analogs. The derivatives of the present invention are also soluble in common organic solvents to facilitate the purification in a large scale synthesis of the composition.

Description

GOVERNMENT INTEREST [0001] The invention described herein may be manufactured, used and licensed by or for the U.S. Government. BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The present invention relates to new compounds that are useful for the treatment of malaria. The compounds of the invention are pyrroloquinazolinediamine derivatives, namely alkyl derivatives, carbamate derivatives, succinimide derivatives, alkylcarboxamides derivatives, including acetamide, phthalimide, and all other amide and imide derivatives of the parent compound 1 and their analogs that are effective and less toxic for treatment of malaria, including but not limited to P. falciparum and P. vivax strains. [0004] 2. Brief Description of Related Art [0005] The current global situation with respect to malaria indicates that about two billion people are exposed to the disease. Each year between 100 to 200 million new cases of infection are reported and approximately 1 to 2 million people d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/519C07D487/02
CPCC07D487/04Y02A50/30
Inventor LIN, AI J.GUAN, JIANZHANG, QUANSKILLMAN, DONALD R.
Owner UNITED STATES OF AMERICA THE AS REPRESENTED BY THE SEC OF THE ARMY
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